FAM135B (family with sequence similarity 135 member B) is a multifunctional protein implicated in cancer progression and cellular stress responses. Primary function: FAM135B acts as a regulator of protein interactions and cellular signaling, with roles in DNA damage response, alternative splicing regulation, and immune activation. Mechanism: FAM135B interacts with multiple partners including GRN, TIP60, SRSF1, and IFI16 to modulate distinct cellular pathways 1 2 3 4. It sustains TIP60-ATM assemblies to promote homologous recombination and non-homologous end-joining DNA repair 2, while also controlling SRSF1-mediated alternative splicing of DNA repair genes to regulate Fanconi anemia pathway activation 3. Additionally, FAM135B stabilizes IFI16 by blocking its ubiquitination, thereby activating STING-dependent cytotoxic T-cell responses 4. Disease relevance: FAM135B is frequently mutated in esophageal squamous cell carcinoma and colorectal cancer 5 3. High FAM135B expression correlates with poor prognosis and chemotherapy/radiotherapy resistance 1 6. Clinical significance: FAM135B represents a potential therapeutic target, with combination strategies targeting FAM135B alongside chemotherapy, radiation, or immunotherapy showing promise for improving cancer treatment outcomes.